Method for coating an implantable device and system for performing the method

ABSTRACT

Methods of coating an implantable device and a system for performing such methods are disclosed. An embodiment of the method includes applying a coating substance to the surface of an implantable device, and rotating the implantable device in a centrifuge. The method can uniformly coat the implantable device with the coating substance and to remove unwanted accumulations of coating substance entrained between struts or crevices in the implantable device body. This system is applicable to methods for coating intraluminal stents, synthetic grafts, and stent coverings with therapeutic compositions comprising therapeutic agents mixed with a polymeric matrix and a solvent.

FIELD OF THE INVENTION

[0001] The present invention relates to the coating of an implantabledevice. More specifically, this invention relates to a centrifuge systemand method for coating of an intraluminal implantable device, such as astent.

BACKGROUND

[0002] Occlusion of blood vessels reduces or blocks blood flow. Duringthe course of atherosclerosis, for example, growths called plaquesdevelop on the inner walls of the arteries and narrow the bore of thevessels. An emboli, or a moving clot, is more likely to become trappedin a vessel that has been narrowed by plaques. Further, plaques arecommon sites of thrombus formation. Together, these events increase therisk of heart attacks and strokes.

[0003] Traditionally, critically stenosed atherosclerotic vessels havebeen treated with bypass surgery in which veins removed from the legs,or small arteries removed from the thoracic cavity, are implanted in theaffected area to provide alternate routes of blood circulation. Morerecently, implantable devices, such as synthetic vascular grafts andstents, have been used to treat diseased blood vessels.

[0004] Synthetic vascular grafts are macro-porous vessel-likeconfigurations typically made of expanded polytetrafluoroethylene(ePTFE), polyethylene terephthalate (PET), polyurethane (PU), or anabsorbable polymer. Grafts made of ePTFE or PET are very non-wettingmaterials when introduced into an aqueous environment, causingdifficulty in impregnating the materials. In addition, grafts made ofePTFE or PET typically are permanently implanted in the body, whilegrafts made of an absorbable polymer bioabsorb over time. A graft may bepositioned into the host blood vessel as a replacement for a diseased oroccluded segment that has been removed. Alternatively, a graft may besutured to the host vessel at each end so as to form a bypass conduitaround a diseased or occluded segment of the host vessel.

[0005] Percutaneous transluminal coronary angioplasty (PTCA) is aprocedure for treating heart disease in which a catheter assembly havinga balloon portion is introduced percutaneously into the cardiovascularsystem of a patient via the brachial or femoral artery. The catheterassembly is advanced through the coronary vasculature until the balloonportion is positioned across the occlusive lesion. Once in positionacross the lesion, the balloon is inflated to a predetermined size toradially compress the atherosclerotic plaque of the lesion against theinner wall of the artery to dilate the lumen. The balloon is thendeflated to a smaller profile to allow the catheter to be withdrawn fromthe patient's vasculature.

[0006] Restenosis of the artery commonly develops over several monthsafter the procedure, which may require another angioplasty procedure ora surgical by-pass operation. Restenosis is thought to involve thebody's natural healing process. Angioplasty or other vascular proceduresinjure the vessel walls, removing the vascular endothelium, disturbingthe tunica intima, and causing the death of medial smooth muscle cells.Excessive neoinitimal tissue formation, characterized by smooth musclecell migration and proliferation to the intima, follows the injury.Proliferation and migration of smooth muscle cells (SMC) from the medialayer to the intima cause an excessive production of extra cellularmatrices (ECM), which is believed to be one of the leading contributorsto the development of restenosis. The extensive thickening of thetissues narrows the lumen of the blood vessel, constricting or blockingblood flow through the vessel.

[0007] Intravascular stents are sometimes implanted within vessels in aneffort to maintain the patency thereof by preventing collapse and/or byimpeding restenosis. Implantation of a stent is typically accomplishedby mounting the stent on the expandable portion of a balloon catheter,maneuvering the catheter through the vasculature so as to position thestent at the desired location within the body lumen, and inflating theballoon to expand the stent so as to engage the lumen wall. The stentautomatically locks into its expanded configuration, allowing theballoon to be deflated and the catheter removed to complete theimplantation procedure. A covered stent, in which a graft-like coveringis slip-fit onto the stent, may be employed to isolate the brittleplaque from direct contact with the stent, which is rigid.

[0008] To reduce the chance of the development of restenosis,therapeutic substances may be administered to the treatment site. Forexample, anticoagulant and antiplatelet agents are commonly used toinhibit the development of restenosis. In order to provide anefficacious concentration to the target site, systemic administration ofsuch medication may be used, which often produces adverse or toxic sideeffects for the patient. Local delivery is a desirable method oftreatment, in that smaller total levels of medication are administeredin comparison to systemic dosages, but are concentrated at a specificsite. Therefore, local delivery may produce fewer side effects andachieve more effective results.

[0009] One commonly applied technique for the local delivery of atherapeutic substance is through the use of a medicated implantabledevice, such as a stent or graft. Because of the mechanical strengthneeded to properly support vessel walls, stents are typicallyconstructed of metallic materials. The metallic stent may be coated witha polymeric carrier, which is impregnated with a therapeutic agent. Thepolymeric carrier allows for a sustained delivery of the therapeuticagent.

[0010] Various approaches have previously been used to join polymers tometallic stents, including dipping and spraying processes. In onetechnique, the stent is first formed in a flat sheet, placed in asolution of polyurethane, and heated for a short period of time.Additional polyurethane solution is applied on top of the flat sheet,and the stent is again heated. This process produces a polyurethane filmover the surface of the stent, and excess film is manually trimmed away.In one variation of this technique, microcapsules containing therapeuticagents are incorporated into the polyurethane film by adding themicrocapsules to the polyurethane solution before heating.

[0011] In another technique, a solution is prepared that includes asolvent, a polymer dissolved in the solvent, and a therapeutic agentdispersed in the solvent. The solution is applied to the stent byspraying the solution onto the stent using an airbrush. After each layeris applied, the solvent is allowed to evaporate, thereby leaving on thestent surface a coating of the polymer and the therapeutic substance.Use of this spraying technique to apply a thick coating may result incoating uniformity problems, so multiple application steps are sometimesused in an attempt to provide better coating uniformity.

[0012] In yet another coating technique, a solution of dexamethasone inacetone is prepared, and an airbrush is used to spray short bursts ofthe solution onto a rotating wire stent. The acetone quickly evaporates,leaving a coating of dexamethasone on the surface of the stent.

[0013] The above-described methods often fail to provide an economicallyviable method of applying an even coating on the stent surfaces. Onecommon result when using these spraying or immersion processes is thatthe aqueous coating tends to collect in crevices, apertures, or cavitiesin the framework of the stent, resulting in an uneven coating having anuncontrollably variable coating thickness. In particular, an excessamount of coating is often entrained in the angle between twointersecting struts of a stent, which is sometimes called “webbing” or“pooling.” The deposition of excessive amounts of therapeutic agentsresults in a poor surface area to volume ratio relative to conformalcoatings. When such a coating experiences uncontrolled drying, dryingartifacts may result in drug crystal formation.

[0014] The use of multiple applications of a fine, diffuse spray mayproduce a more controllable, even coating than immersion techniques.However, the diffuse application results in much of the coatingsubstance not coating the stent and instead being released into the air.This inefficient use of the coating substance wastes the coatingsubstance, which may be quite expensive, and increases the exposure ofthe air brush operator to the coating substance.

[0015] Accordingly, there is a need for an improved method for coatingmedical devices which produces superior coating uniformity without anexcessive loss of materials.

SUMMARY

[0016] In accordance with an aspect of the present invention, a methodfor coating a implantable device includes applying a coating substanceon a surface of said implantable device, and rotating said implantabledevice about an axis of rotation. A centrifuge system may be used torotate the prosthesis. The implantable device may be a stent, graft, orstent covering. The coating substance may be applied using a variety oftechniques, including immersion or spraying, among other possibilities.The method may further include collecting runoff coating substance in arunoff reservoir of the centrifuge system while rotating the implantabledevice. This collected runoff coating substance may then be recycled andused to coat a second implantable device, thus avoiding waste of thecoating substance.

[0017] Another embodiment of the present invention includes a centrifugesystem for coating an implantable device. The centrifuge system includesa rotor having an axis of rotation, said rotor including a plurality ofchambers. A motor is operably connected to said rotor for rotating saidrotor. A plurality of centrifuge containers are each received in one ofsaid plurality of chambers in said rotor. A plurality of mandrels areeach mounted in one of said plurality of centrifuge containers andadapted to receive an implantable device.

[0018] Embodiments of the present invention can be used to coat avariety of implantable devices with aqueous or solvent-based coatingsubstances. In particular, certain embodiments can be used to coatstents with therapeutic or bioactive substances, such as compositions ofa polymer, solvent, and therapeutic substance.

BRIEF DESCRIPTION OF THE DRAWINGS

[0019] The present invention may be better understood, and its numerousobjects, features, and advantages made apparent to those skilled in theart, by referencing the accompanying drawings.

[0020]FIG. 1 illustrates in plan view a cross-section of a centrifugesystem in accordance with an embodiment of the present invention.

[0021]FIG. 2 is a cross-section in plan view of a centrifuge containerin accordance with an embodiment of the present invention.

[0022]FIG. 3 is a flowchart of a coating process in accordance with anembodiment of the present invention.

[0023] The use of the same reference symbols in different drawingsindicates similar or identical items.

DETAILED DESCRIPTION

[0024] The following description is meant to be illustrative only andnot limiting. Other embodiments of this invention will be apparent tothose of ordinary skill in the art in view of this description.

[0025] The figures generally illustrate the techniques used to applycoatings to a stent in accordance with an embodiment of the presentinvention. Although the illustrated and described embodiments may relateto wire-based stents, any of a variety of implantable devices may besubjected to the coating process described herein, including, but notlimited to, wire-based stents, tubular stents, rolled-sheet type stents,stent coverings, vascular grafts, or any implantable device having acomplicated architecture which is not amenable to standard coating.

[0026] The materials from which such stents are formed may includemetals such as, but not limited to, stainless steel, “MP35N,” “MP20N,”elastinite (Nitinol), tantalum, nickel-titanium alloy, platinum-iridiumalloy, gold, magnesium, or combinations thereof. “MP35N” and “MP20N” aretrade names for alloys of cobalt, nickel, chromium and molybdenumavailable from standard Press Steel Co., Jenkintown, PA. “MP35N”consists of 35% cobalt, 35% nickel, 20% chromium, and 10% molybdenum.“MP20N” consists of 50% cobalt, 20% nickel, 20% chromium, and 10%molybdenum. The stent also may be made from virtually any bio-compatiblematerial, such as bioabsorbable or biostable polymers.

[0027] Vascular grafts may be used to replace, bypass, or reinforcediseased or damaged sections of a vein or artery. These grafts can bemade from any suitable material including, but not limited to, highlyopen-pored materials such as polymers of expandedpolytetrafluoroethylene (ePTFE) and polyethylene terephthalate (PET), orless porous materials such as polyurethanes, absorbable polymers, andcombinations or variations thereof. Grafts may be formed using alyophilization process. Polyurethanes from which the graft may be madeinclude, but are not limited to, Biomer, Biospan, and Elastion.

[0028] Absorbable polymers from which the graft may be made include, butare not limited to, polycaprolactone (PCL), poly(lactic acid) (PLA),poly(glycolic acid) (PGA), polyanhydrides, polyorthoesters,polyphosphazenes, and components of extracellular matrix (ECM). In suchan embodiment, additional interstices can be formed in the graft by anyconventional methods known to one of ordinary skill in the art,including exposure of the graft to a laser discharge to form a patternof pores.

[0029] In other embodiments, the implantable device to be coated is acovering for a self-expandable or balloon-expandable stent. Thiscovering can be formed of materials similar to those from which theabove-described graft may be formed.

[0030] Various types of coating substances may be applied to animplantable device in accordance with the present invention. In oneembodiment, the coating substance includes a polymer loaded with atherapeutic substance. The terms “polymer,” “poly,” and “polymeric” asused herein mean the product of a polymerization reaction and areinclusive of homopolymers, copolymers, terpolymers, etc., whethernatural or synthetic, including random, alternating, block, graft,crosslinked, blends, compositions of blends and variations thereof. Theterm “pre-polymer” refers to a reactive polymer that has not yet beencrosslinked.

[0031] The polymer or combination of polymers can be applied to a stentbased on the polymer's or polymers' ability to carry and release, at acontrolled rate, various therapeutic agents such as antithrombogenic oranti-proliferative drugs. The polymeric material is most suitablybio-compatible, including polymers that are non-toxic, non-inflammatory,chemically inert, and substantially non-immunogenic in the appliedamounts. The polymer is typically either bioabsorbable or biostable. Abioabsorbable polymer breaks down in the body and is not presentsufficiently long after implantation to cause an adverse local response.Bioabsorbable polymers are gradually absorbed or eliminated by the bodyby hydrolysis, metabolic process, bulk, or surface erosion. Examples ofbioabsorbable materials include but are not limited to polycaprolactone(PCL), poly-D, L-lactic acid (DL-PLA), poly-L-lactic acid (L-PLA),poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,polyanhydride, poly(glycolic acid), poly(glycolic acid-cotrimethylenecarbonate), polyphosphoester, polyphosphoester urethane, poly (aminoacids), cyanoacrylates, poly(trimethylene carbonate),poly(iminocarbonate), copoly(ether-esters), polyalkylene oxalates,polyphosphazenes, polyiminocarbonates, and aliphatic polycarbonates.Biomolecules such as heparin, fibrin, fibrinogen, cellulose, starch, andcollagen are typically also suitable. Examples of biostable polymersinclude Parylene® and Parylast® (available from Advanced SurfaceTechnology of Billerica, MA), polyurethane, such as a segmentedpolyurethane solution containing a dimethylacetamide (DMAc) solventdeveloped by the Polymer Technology Group, Inc. of Berkeley, Calif., andknown by the trade name BioSpan®, polyethylene, polyethlyeneteraphthalate, ethylene vinyl acetate, silicone and polyethylene oxide(PEO).

[0032] The expression “therapeutic agent” as used herein broadly refersto an agent or substance that possesses desirable therapeuticcharacteristics. The therapeutic agent may be, for example,antineoplastic, antimitotic, antiinflammatory, antiplatelet,anticoagulant, antifibrin, antithrombin, antiproliferative, antibiotic,antioxidant, and antiallergic substances, as well as combinationsthereof. Examples of such antineoplastics and/or antimitotics includepaclitaxel (e.g., TAXOL® by Bristol-Myers Squibb Co., Stamford, Conn.),docetaxel (e.g., Taxotere® from Aventis S.A., Frankfurt, Germany)methotrexate, azathioprine, vincristine, vinblastine, fluorouracil,doxorubicin hydrochloride (e.g., Adriamycin® from Pharmacia & Upjohn,Peapack, N.J.), and mitomycin (e.g., Mutamycin® from Bristol-MyersSquibb Co., Stamford, Conn.). Examples of such antiplatelets,anticoagulants, antifibrin, and antithrombins include sodium heparin,low molecular weight heparins, heparinoids, hirudin, argatroban,forskolin, vapiprost, prostacyclin and prostacyclin analogues, dextran,D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole,glycoprotein IIb/IIIa platelet membrane receptor antagonist antibody,recombinant hirudin, and thrombin inhibitors such as Angiomax™(Biogen,Inc., Cambridge, Mass.). Examples of such cytostatic orantiproliferative agents include angiopeptin, angiotensin convertingenzyme inhibitors such as captopril (e.g., Capoten® and Capozide® fromBristol-Myers Squibb Co., Stamford, Conn.), cilazapril or lisinopril(e.g., Prinivil® and Prinzide® from Merck & Co., Inc., WhitehouseStation, N.J.); calcium channel blockers (such as nifedipine),colchicine, fibroblast growth factor (FGF) antagonists, fish oil (omega3-fatty acid), histamine antagonists, lovastatin (an inhibitor ofHMG-CoA reductase, a cholesterol lowering drug, brand name Mevacor® fromMerck & Co., Inc., Whitehouse Station, N.J.), monoclonal antibodies(such as those specific for Platelet-Derived Growth Factor (PDGF)receptors), nitroprusside, phosphodiesterase inhibitors, prostagiandininhibitors, suramin, serotonin blockers, steroids, thioproteaseinhibitors, triazolopyrimidine (a PDGF antagonist), and nitric oxide. Anexample of an antiallergic agent is permirolast potassium. Othertherapeutic substances or agents that may be used includealpha-interferon, genetically engineered epithelial cells, anddexamethasone.

[0033] While the preventative and treatment properties of the foregoingtherapeutic substances or agents are well-known to those of ordinaryskill in the art, the substances or agents are provided by way ofexample and are not meant to be limiting. Other therapeutic substancesare equally applicable for use with the disclosed embodiments. Forexample, while many of the herein-described therapeutic agents have beenused to prevent or treat restenosis, they are provided by way of exampleand are not meant to be limiting, since other drugs or coatings may bedeveloped which are equally applicable for use with embodiment of thepresent invention.

[0034] In other embodiments, the coating is an aqueous solution of atherapeutic substance that does not contain a polymer matrix, such as,for example, an aqueous solution of heparin. This aqueous solution canbe applied to the stent in accordance with the present invention andallowed to dry, thereby forming a heparin coating on the stent.

[0035] In addition to a polymer and a therapeutic agent, the coatingsubstance may also include a solvent. The solvent can be virtually anysolvent that is compatible with the implantable device to be coated.Examples of suitable solvents include but are not limited to dimethylsulfoxide, dimethyl formamide, tetrahydroforan, dimethyl acetamide,trichloroethane, acetone, ethanol, methanol, isopropanol, and ethylacetate.

[0036]FIG. 1 shows a cross-section of an exemplary centrifuge system 100in accordance with an embodiment of the present invention. Centrifugesystem 100 includes a centrifuge device 102, which includes a rotatablerotor 104 for rotation about an axis 106, and a motor 108 which drivesrotor 104 to rotate about axis 106. Centrifuge models 5410, 5415, 5417,5804, and 5810, sold by Eppendorf Scientific, Inc., of Westbury, N.Y.,may be used, for example, as centrifuge device 102. Exemplary centrifugedevices 102 provide rotational speeds of up to, for example, 14,000rotations per minute (“RPM”). Rotor 104 includes a plurality of hollowchambers 110 circularly arranged about axis 106. Each chamber 110 issized to receive a centrifuge container 112. Various centrifuge devices102 available on the market are capable of centrifuging large numbers ofcentrifuge containers 112 simultaneously.

[0037]FIG. 2 shows in greater detail a cross-section of an exemplarycentrifuge container 112. Centrifuge container 112 can be formed using aconventional centrifuge tube that has been modified as described below.A support 202 is provided towards the bottom of centrifuge container112, and a mandrel 204 is mounted thereon. In this embodiment, mandrel204 is a rod. Mandrel 204 is inserted into the interior of theimplantable device to be coated, such as a cylindrical stent 206.Mandrel 204 holds stent 206 and prevents stent 206 from contacting theinterior walls of centrifuge container 112. Support 202 separates stent206 from runoff reservoir 208, which is provided at the bottom ofcentrifuge container 112. Drainage openings 210 may be provided insupport 202.

[0038] As can be seen in the embodiment shown in FIGS. 1-2, mandrel 204is tilted such that when each centrifuge container 112 is mounted incentrifuge system 100, stents 206 are positioned such that theirlongitudinal axes are nearly parallel to axis of rotation 106. This mayprovide a more even coating on stents 206 after centrifugation. Inalternative embodiments, mandrels 204 may have a different tilt anglerelative to the central axes of centrifuge containers 112, or may haveno tilt at all.

[0039]FIG. 3 is a flowchart illustrating an exemplary method of coatingan implantable device in accordance with an embodiment of the presentinvention. For the sake of example, the implantable device describedwith respect to FIGS. 1-3 is a stent, but the method also may be appliedto various other implantable devices discussed above.

[0040] In act 301, a first coating is applied to stent 206. The coatingmay be applied by spraying or immersing stent 206 with an aqueouscoating substance using techniques similar to those described in thebackground section above. The term “aqueous” as used herein refers tosubstances having sufficient fluidity such that the substance can flowover the surface of stent 206 when processed through the further actsdescribed below. “Aqueous” is not intended to limit the coatingsubstance to water-based substances or to low viscosity materials. Evenhighly viscous substances such as a hyaluronic acid solution (e.g., 1%hyaluronic acid), high molecular weight polyethylene glycol solution,gelatin solution, or poly (lactic) acid in 1, 1, 2 trichloroethane(e.g., 10% poly (lactic) acid) are included within the term.

[0041] As with conventional coating techniques, the spraying orimmersion of stent 206 in the coating substance typically results in anon-uniform coating, with webbing being observable between struts onstent 206. In act 302, the still-wet stent 206 is inserted onto mandrel204 in centrifuge container 112 such that mandrel 204 extends throughthe hollow interior of stent 206. Centrifuge container 112 is theninserted into chamber 110 of centrifuge system 100 (FIG. 1), andcentrifuge system 100 is used to rotate stent 206 about axis 106 at highspeeds. Centrifuge system 100 includes a plurality of rotatable chambers110, such that multiple coated stents 206 can be centrifugedsimultaneously, thereby increasing processing throughput.

[0042] The rotation of chambers 110 at high speeds creates a centrifugalforce upon the coating substance that previously was applied to thesurface of stent 206. This centrifugal force causes excess accumulationsof coating substance, particularly the portions entrained between thestruts of stent 206, to be more evenly redistributed over stent 206.This redistribution of the coating substance over the surface of stent206 provides a more uniform coating free of webbing.

[0043] The centrifugation of stent 206 may result in some excess coatingsubstance being removed from the surface of stent 206. Drainage openings210 are provided in support 202 so that the runoff coating substance canflow from the upper portion of centrifuge container 112 into runoffreservoir 208. The channeling of runoff coating substance into runoffreservoir 208 prevents the coating substance from accumulating at thebottom end 212 of stent 206, which could lead to a non-uniform coating.This runoff coating substance can be recovered from runoff reservoir 208and reused to coat additional stents 206. The recycling of the coatingsubstance can produce significant cost savings when an expensivetherapeutic agent is being used.

[0044] In alternative embodiments, different structures are provided toeffectuate the flow of runoff coating substance into runoff reservoir208. In one embodiment, support 202 is square-shaped, such that whensupport 202 is fitted into a centrifuge container 112 which iscylindrical in shape, runoff coating substance can flow around theopenings formed between the edges of square support 202 and the circularinterior of centrifuge container 112. In another embodiment, support 202comprises a mesh platform, such that fluid can freely flow throughsupport 202 to pass into reservoir 208. Numerous other variations arepossible.

[0045] In act 303, coated, centrifuged stent 206 is immediately placedinto a convention oven for heating. This heating evaporates solventsthat might be present in the coating substance, thereby forming a solidcoating on the surface of stent 206. Heating act 303 can improve theadhesion of the coating substance to the metal forming metallic stents206, and can also provide a better equilibrium for the solid phase drugdistribution in the matrix of the coating substance. Heating act 303might be used, for example, when coating stent 206 with a composition ofethylene vinyl alcohol copolymer with dimethyl sulfoxide, as will bedescribed in greater detail in the example below. In alternativeembodiments, no heating act is used, and stent 206 may be implantedimmediately after centrifugation act 302. The use of a heating step, andthe parameters of such a step will vary with the application.

[0046] In act 304, it is determined whether one or more additionallayers of coating substance is to be applied to stent 206. If so, theprocess returns to act 301, and another layer of coating substance isapplied. Multiple layers of coating substance may be applied in order toproduce a more uniform coating with fewer defects. Each layer can beformed very thin and uniform, and subsequent layers can be added toincrease the overall loading onto stent 206. Moreover, the use ofmultiple layers can provide enhanced control over the release rate ofthe coating. Finally, when the desired number of layers have beenapplied, the process is completed at act 305, and stent 206 may bepackaged for delivery or immediately implanted into a patient's bodyusing techniques well-known to those of ordinary skill in the art.

[0047] Grafts and stent coverings may include a large number ofinterstices, which cause these devices to have a generally permeablecharacteristic. In accordance with various embodiments of the presentinvention, permeable grafts and stent coverings can be coated with acoating substance, such as those described above, and then placed into acentrifuge for centrifugation. The centrifugation process provides canprovide improved perfusion of the coating substance through theinterstices of the graft or stent covering, particularly when thedevices are formed of a highly hydrophobic material.

[0048] In another embodiment, a process for applying a hydrogel coatingto a graft or stent covering is provided. When applying a hydrogelcoating, a coating substance containing at least one crosslinkablepre-polymer and a first fluid in which the pre-polymer is soluble isprepared. The pre-polymer should be in true solution, saturated, orsuper-saturated with the first fluid. Exemplary crosslinkablepre-polymers include, but are not limited to, polyethylene glycol (PEG)diacrylate, hyaluronic, and pluronic. The concentration of pre-polymerin the composition should be selected such that it is high enough toensure effective crosslinking of the pre-polymer since a solution toodilute may not form a crosslinked hydrogel. An implantable device maythen be dipped into this pre-polymer coating substance. Alternatively,prior to application of the pre-polymer, the implantable device may beperfused with a low surface energy solvent such as, for example, acetoneor ethanol, which effectuates improved perfusion of the pre-polymersolution through the interstices of the implantable device.

[0049] After the implantable device is dipped into the pre-polymersolution, the implantable device is placed in a centrifuge container andloaded into a centrifuge system, similar to the centrifuge container 112and centrifuge system 100 described above. Centrifuging the coatedimplantable device spreads the viscous pre-polymer solution evenlyacross the surface of the implantable device and into the interstices orcrevices therein.

[0050] Finally, the pre-polymer is cured to form a hydrogel coating onthe implantable device. Curing may be accomplished photochemically usingultraviolet or visible irradiation and a photoinitiator, thermally, orby moisture curing at room temperature. The practice of these and othersuitable curing procedures is well known to those of ordinary skill inthe art.

[0051] In yet another embodiment, the coating method of the presentinvention can be used to provide a physician with greater flexibility inselecting a desired coating substance for use with a particular patient.Conventionally, stents are coated by either the stent manufacturer or athird party prior to delivering the stent to a physician forimplantation into a patient. In accordance with the present invention, aphysician can apply a coating on a bare stent, centrifuge the stentusing a small, portable centrifuge device, and implant thefreshly-prepared stent in a patient's body. This enables the physicianto precisely select the composition of the coating substance applied tothe stent. In addition, because the stent can be locally coated and thenimmediately implanted by the physician after coating, perishable orenvironmentally-sensitive materials may be used to coat the stent.

EXAMPLE

[0052] In one example, fifteen 13 mm ACS Multi-Link Duet® stainlesssteel stents, produced by the Guidant Corp. of Indianapolis, Ind., areimmersed (e.g., for a few seconds or up 20 seconds or more) in a coatingsubstance including ethylene vinyl alcohol copolymer (commonly known bythe generic name EVOH or by the trade name EVAL) and dimethyl sulfoxide(“DMSO”) solvent, in a 1:4 ratio. Tetrahydrofuran (THF) may be includedin the DMSO. The THF lowers the viscosity of the coating substance andincreases wetting on the surface of stent 206. Each of the fifteenstents is then immediately mounted into a centrifuge container 112, asdescribed above with respect to FIGS. 1-3. The fifteen centrifugecontainers 112 are inserted into chambers 110, and centrifuge containers112 are rotated for 60 seconds at 6,500 RPM.

[0053] The stents are then removed from centrifuge containers 112,placed on mandrels, and loaded into a Blue M model vacuum convectionoven from the Blue M Electric company of Watertown, Wis., for 24 hoursat a temperature of 65° C. The heating causes the DMSO in the coatingsubstance to fully evaporate, leaving a thin coating of EVOH on thestents. Alternative forms of heating may also be used, such as the useof a “hot plate” heating surface.

[0054] Next, the immersion, centrifugation, and heating acts can berepeated (e.g., up to four times or more), depending on the thickness ofcoating desired. For these subsequent processes, the stents are immersedin the 1:4 solution of EVOH and DMSO.

[0055] The above-described process results in a white, frosty coating onthe test stents. After two coating cycles, the weight of the coatingdeposited on the stents ranged from approximately 0.066-0.080 Mg and thethickness ranged from approximately 0.5 to 1.5 μm.

[0056] The rotational speed during centrifugation can be varied. HigherRPM values may provide improved uniformity and a reduction in defects.However, lower RPM values may improve solid uptake, i.e., the totalloading of the coating substance onto stent 206. The solid uptake iscalculated by measuring the initial weight of stent 206, and thenmeasuring the weight after the loading and centrifugation acts.Increasing the total centrifugation time may also improve the uniformityand reduce defects in the coating. Accordingly, practitioners shouldtailor the process to the particular application.

[0057] Embodiments of the present invention enable highly viscousmaterials to be coated onto implantable devices. Viscous materials arenot usually amenable to conventional coating methods such as dipping orspraying, because of the viscous material's propensity to accumulate inan uneven layer. However, the addition of a centrifugation step afterdipping the implantable device in the viscous coating material cantransform the uneven masses into a smooth, even coating.

[0058] Embodiments of the present invention also enable uniform coatingsto be applied to implantable devices with improved repeatability,thereby improving coating uniformity between batches of implantabledevices. With conventional manually-applied spray-coating techniques,operator error or inconsistency may result in different coatingthicknesses between batches of stents. The centrifugation processes canreduce unwanted gross deposition of coating substances and enable highreproducibility of the coating quality.

[0059] Embodiments of the present invention also enable multiple stentsto be processed simultaneously. Unlike manually-applied airbrush coatingmethods, in which stents are coated individually or in small groups,large batches of stents can be simultaneously immersed in the coatingsolution, simultaneously rotated in the centrifuge device, andsimultaneously heated in an oven, thereby increasing throughput.

[0060] Embodiments of the present invention also may improve operatorsafety when coating implantable devices with hazardous materials. It isgenerally not desirable to spray coat an implantable device with toxicor radioactive coating substances, because of the increased exposure ofthe operator to the airborne hazardous coating substance. Dipping andcentrifuging the implantable device as described above can decrease theamount of handling required for the coating process, resulting in lessenvironmental contamination.

[0061] Embodiments of the present invention may also reduce defects dueto handling of the implantable device. In conventional spray processes,the implantable device is held aloft using one or two clamps or fixtureswhile the coating substance is sprayed onto the device. The point wherethese clamps contact the device may result in defects in the coating. Incontrast, the centrifuge container 112 results in minimal contact withthe implantable device during the centrifuge process.

[0062] The above embodiments only illustrate the principles of thisinvention and are not intended to limit the invention to the particularembodiments described. For example, the heating acts used to evaporatethe solvent material may be omitted, and other embodiments utilizingcentrifugation coating methods can be used in combination with otheracts in different processes which do not require active heating. Theseand various other adaptations and combinations of features of theembodiments disclosed are within the scope of the invention, as definedby the following claims.

I claim:
 1. A method for coating an implantable device, comprising: applying a coating substance on a surface of said implantable device; and rotating said implantable device about an axis of rotation.
 2. The method of claim 1, wherein said implantable device is a stent.
 3. The method of claim 1, wherein said implantable device is a graft.
 4. The method of claim 1, wherein said implantable device is a covering for a stent.
 5. The method of claim 1, wherein said applying said coating substance comprises immersing said implantable device in said coating substance.
 6. The method of claim 1, wherein said applying said coating substance comprises spraying said coating substance onto said surface of said implantable device.
 7. The method of claim 1, further comprising heating said implantable device after rotating said implantable device about said axis of rotation.
 8. The method of claim 1, wherein said rotating is performed in a centrifuge device.
 9. The method of claim 8, further comprising: positioning said implantable device in a centrifuge container; and loading said centrifuge container into said centrifuge device.
 10. The method of claim 9, further comprising: while rotating said implantable device about said axis of rotation, collecting runoff coating substance.
 11. The method of claim 10, further comprising: recycling said collected runoff coating substance.
 12. The method of claim 1, wherein said coating substance includes a polymer, a solvent, and a therapeutic agent.
 13. The method of claim 12, wherein said polymer is one of the group consisting of: ethylene vinyl alcohol, polyurethane, heparin, polycaprolactone, and poly-lactic acid.
 14. The method of claim 12, wherein said solvent is one of the group consisting of: dimethyl sulfoxide, dimethyl formamide, tetrahydroforan, dimethyl acetamide, and trichloroethane.
 15. The method of claim 12, wherein said therapeutic agent is one of the group consisting of: antinomycin-D, trapidil, heparin, dexamethasone, and paclitaxel.
 16. The method of claim 1, wherein said coating substance contains a crosslinkable pre-polymer, and further comprising: curing said crosslinkable pre-polymer to form a hydrogel.
 17. The method of claim 1, wherein: said applying said coating substance comprises applying said coating substance to a surface of a plurality of implantable devices; and said rotating said implantable device comprises simultaneously rotating said plurality of implantable devices.
 18. An implantable device formed by the method of claim
 1. 19. A centrifuge system for coating a stent, comprising: a rotor having an axis of rotation, said rotor including a plurality of chambers; a motor operably connected to said rotor for rotating said rotor; a plurality of centrifuge containers, each centrifuge container being received in one of said plurality of chambers in said rotor; and a plurality of mandrels, each mandrel mounted in one of said plurality of centrifuge containers and adapted to receive an implantable device.
 20. The centrifuge system of claim 19, further comprising: a plurality of implantable devices, each implantable device being received by one of said plurality of mandrels.
 21. The centrifuge system of claim 19, wherein each of said centrifuge containers further comprises: a runoff reservoir region provided at a bottom of said centrifuge container; and a support arranged in an interior region of said centrifuge container for supporting an implantable device above said runoff reservoir region.
 22. The centrifuge system of claim 20, wherein said plurality of implantable devices comprises a plurality of stents.
 23. The centrifuge system of claim 20, wherein said plurality of implantable devices comprises a plurality of grafts.
 24. The centrifuge system of claim 20, wherein said plurality of implantable devices comprises a plurality of stent coverings. 